tbuckley/cabot-search huggingface dataset:
Congressional Testimony
Journal: JAMA (2023)

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Transparent reporting of multivariable prediction models developed or validated using clustered data (TRIPOD-Cluster): explanation and elaboration
Authors: Thomas P A Debray, Gary S Collins, Richard D Riley, Kym I E Snell, Ben Van Calster, Johannes B Reitsma, Karel G M Moons
Journal: BMJ (2023)

The TRIPOD-Cluster (transparent reporting of multivariable prediction models developed or validated using clustered data) statement comprises a 19 item checklist, which aims to improve the reporting of studies developing or validating a prediction model in clustered data, such as individual participant data meta-analyses (clustering by study) and electronic health records (clustering by practice or hospital). This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD-Cluster statement is explained in detail and accompanied by published examples of good reporting. The document also serves as a reference of factors to consider when designing, conducting, and analysing prediction model development or validation studies in clustered data. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, authors are recommended to include a completed checklist in their submission.
How can I deal with guilt over being off work sick?
Authors: Adele Waters
Journal: BMJ (2023)

How can I deal with guilt over being off work sick?Doctors often feel huge guilt when they are ill and unable to work.Adele Waters asks what can help to ease that burden Adele WatersWe have a responsibility to model good self-care Helen Garr, medical director, NHS Practitioner Health, says, "There's no lesson at medical school that teaches us to come to work when we're unwell.But somewhere along the way we've learnt as a profession to feel guilty when needing time off, often underpinned by the unwavering need not to let down our colleagues or our patients.
Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs
Authors: Beatriz F. Côrte-Real, Ibrahim Hamad, Rebeca Arroyo Hornero, Sabrina Geisberger, Joris Roels, Lauren Van Zeebroeck, Aleksandra Dyczko, Marike W. van Gisbergen, Henry Kurniawan, Allon Wagner, Nir Yosef, Susanne N.Y. Weiss, Klaus G. Schmetterer, Agnes Schröder, Luka Krampert, Stefanie Haase, Hendrik Bartolomaeus, Niels Hellings, Yvan Saeys, Ludwig J. Dubois, Dirk Brenner, Stefan Kempa, David A. Hafler, Johannes Stegbauer, Ralf A. Linker, Jonathan Jantsch, Dominik N. Müller, Markus Kleinewietfeld
Journal: Cell Metabolism (2023)
Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis
Authors: Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee
Journal: Cell Metabolism (2023)

Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET
Authors: Qilin Zhang, Boyuan Yao, Xin Long, Zhengyuan Chen, Min He, Yue Wu, Nidan Qiao, Zengyi Ma, Zhao Ye, Yichao Zhang, Shun Yao, Ye Wang, Haixia Cheng, Hong Chen, Hongying Ye, Yongfei Wang, Yimin Li, Jianhua Chen, Zhaoyun Zhang, Fan Guo, Yao Zhao
Journal: Cell Reports Medicine (2023)

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors with variable recurrence rate. Currently, the recurrence prediction is unsatisfying and can be improved by understanding the cellular origins and differentiation status. Here, to comprehensively reveal the origin of PitNET, we perform comparative analysis of single-cell RNA sequencing data from 3 anterior pituitary glands and 21 PitNETs. We identify distinct genes representing major subtypes of well and poorly differentiated PitNETs in each lineage. To further verify the predictive value of differentiation biomarkers, we include an independent cohort of 800 patients with an average follow-up of 7.2 years. In both PIT1 and TPIT lineages, poorly differentiated groups show significantly higher recurrence rates while well-differentiated groups show higher recurrence rates in SF1 lineage. Our findings reveal the possible origin and differentiation status of PitNET based on which new differentiation classification is proposed and verified to predict tumor recurrence.
The role of digital technology in surgical home hospital programs
Authors: Kavya Pathak, Jayson S. Marwaha, Thomas C. Tsai
Journal: npj Digital Medicine (2023)

Abstract Home hospital (HH), a care delivery model of providing hospital-grade care to patients in their homes, has become increasingly common in medical settings, though surgical uptake has been limited. HH programs have been shown to be safe and effective in a variety of medical contexts, with increased usage of this care pathway during the COVID-19 pandemic. Though surgical patients have unique clinical considerations, surgical Home Hospital (SHH) programs may have important benefits for this population. Various technologies exist for the delivery of hospital care in the home, such as clinical risk prediction models and remote patient monitoring platforms. Here, we use institutional experiences at Brigham and Women’s Hospital (BWH) to discuss the utility of technology in enabling SHH programs and highlight current limitations. Additionally, we comment on the importance of data interoperability, access for all patients, and clinical workflow design in successfully implementing SHH programs.
Examining the Acute Glycemic Effects of Different Types of Structured Exercise Sessions in Type 1 Diabetes in a Real-World Setting: The Type 1 Diabetes and Exercise Initiative (T1DEXI)
Authors: Michael C. Riddell, Zoey Li, Robin L. Gal, Peter Calhoun, Peter G. Jacobs, Mark A. Clements, Corby K. Martin, Francis J. Doyle III, Susana R. Patton, Jessica R. Castle, Melanie B. Gillingham, Roy W. Beck, Michael R. Rickels, Michael C. Riddell, Michael R. Rickels, Roy W. Beck, Jessica R. Castle, Peter Calhoun, Mark A. Clements, Francis J. Doyle, Robin L. Gal, Melanie B. Gillingham, Peter G. Jacobs, Zoey Li, Corby K. Martin, Susana R. Patton, Deniz Dalton, Laura E. Bocchino, Lindsey C. Beaulieu, Steven Bell, Brian Bugielski, Gabriela Cardenas Villamil, Ellis L. Greene, Russell Guzzetta, Anna Mazzuoccolo, Kyle Shaver, Karissa Neubig, Suna Onengut-Gumuscu, Stephen S. Rich, Wei-Men Chen, Joe Pinsonault, Joseph Leitschuh, Sos Oganessian, Eleonora Aiello, Matt Heelan, Lisa Sanesanong, Brian “Mooose” Rivera, Harpreet Gill, Avinash Kollu, Earl Glynn, Brent Lockee, Mitchell Barnes
Journal: Diabetes Care (2023)

Maintenance of glycemic control during and after exercise remains a major challenge for individuals with type 1 diabetes. Glycemic responses to exercise may differ by exercise type (aerobic, interval, or resistance), and the effect of activity type on glycemic control after exercise remains unclear.The Type 1 Diabetes Exercise Initiative (T1DEXI) was a real-world study of at-home exercise. Adult participants were randomly assigned to complete six structured aerobic, interval, or resistance exercise sessions over 4 weeks. Participants self-reported study and nonstudy exercise, food intake, and insulin dosing (multiple daily injection [MDI] users) using a custom smart phone application and provided pump (pump users), heart rate, and continuous glucose monitoring data.A total of 497 adults with type 1 diabetes (mean age ± SD 37 ± 14 years; mean HbA1c ± SD 6.6 ± 0.8% [49 ± 8.7 mmol/mol]) assigned to structured aerobic (n = 162), interval (n = 165), or resistance (n = 170) exercise were analyzed. The mean (± SD) change in glucose during assigned exercise was -18 ± 39, -14 ± 32, and -9 ± 36 mg/dL for aerobic, interval, and resistance, respectively (P < 0.001), with similar results for closed-loop, standard pump, and MDI users. Time in range 70-180 mg/dL (3.9-10.0 mmol/L) was higher during the 24 h after study exercise when compared with days without exercise (mean ± SD 76 ± 20% vs. 70 ± 23%; P < 0.001).Adults with type 1 diabetes experienced the largest drop in glucose level with aerobic exercise, followed by interval and resistance exercise, regardless of insulin delivery modality. Even in adults with well-controlled type 1 diabetes, days with structured exercise sessions contributed to clinically meaningful improvement in glucose time in range but may have slightly increased time below range.
Liver Disease in α1-Antitrypsin Deficiency
Authors: John N. Udall
Journal: JAMA (1985)

We identified children with α<sub>1</sub>-antitrypsin deficiency from the medical records of the Massachusetts General Hospital and Children's Hospital, Boston, and investigated their early feeding history. Between 1969 and 1983, forty children with the deficiency were seen at one or both hospitals. Clinical information was obtained from hospital records and from questionnaires mailed to the parents. Complete morbidity, mortality, and early feeding data were obtained for 32 of the children who were born at 38 to 42 weeks' gestation and whose weights were appropriate for gestational age. We compared the presence of severe liver disease and the death rate of those who had been exclusively breast-fed for one month with those who had been bottle-fed. Severe liver disease was present in eight (40%) of bottle-fed and one (8%) of breast-fed infants. Twenty-four of the 32 infants were still alive at the termination of the study; 12 had been breast-fed and 12 bottle-fed during their first month of life. All eight deceased infants had been bottle-fed. The mortality rate in the bottle-fed group was significantly greater than that of the breast-fed group. Our study suggests that breast-feeding may offer some protection against severe liver disease and early death in infants with α<sub>1</sub>-antitrypsin deficiency. (<i>JAMA</i>1985;253:2679-2682)
Adoptive cellular immunotherapy for solid neoplasms beyond CAR-T
Authors: Qiaofei Liu, Jiayi Li, Huaijin Zheng, Sen Yang, Yuze Hua, Nan Huang, Jorg Kleeff, Quan Liao, Wenming Wu
Journal: Molecular Cancer (2023)

Abstract In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However, both show limited efficacies in most solid neoplasms, which necessitates the exploration of new immunotherapeutic modalities. The failure of CAR-T and immune checkpoint blockade in several solid neoplasms is attributed to multiple factors, including low antigenicity of tumor cells, low infiltration of effector T cells, and diverse mechanisms of immunosuppression in the tumor microenvironment. New adoptive cell therapies have been attempted for solid neoplasms, including TCR-T, CAR-natural killer cells (CAR-NK), and CAR-macrophages (CAR-M). Compared to CAR-T, these new adoptive cell therapies have certain advantages in treating solid neoplasms. In this review, we summarized the 40-year evolution of adoptive cell therapies, then focused on the advances of TCR-T, CAR-NK, and CAR-M in solid neoplasms and discussed their potential clinical applications.
DNA transposon mechanisms and pathways of genotoxicity
Authors: Frederic D. Bushman
Journal: Molecular Therapy (2023)

Recently two lymphomas were reported in a chimeric antigen receptor (CAR) T cancer therapy trial (the CARTELL study) 1 Micklethwaite K.P. Gowrishankar K. Gloss B.S. Li Z. Street J.A. Moezzi L. Mach M.A. Sutrave G. Clancy L.E. Bishop D.C. et al. Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood. 2021; 138: 1391-1405 Crossref PubMed Scopus (58) Google Scholar ,2 Bishop D.C. Clancy L.E. Simms R. Burgess J. Mathew G. Moezzi L. Street J.A. Sutrave G. Atkins E. McGuire H.M. et al. Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood. 2021; 138: 1504-1509 Crossref PubMed Scopus (52) Google Scholar in which the piggyBac DNA transposon was used to deliver an engineered receptor gene to human T cells. The transformed cells were found to contain multiple integrated transposon DNA copies (4–24 per cell) and harbor multiple rearrangements in cellular chromosomal DNA. A variety of factors may have contributed to transformation, including aspects of the vector design and cell processing. 1 Micklethwaite K.P. Gowrishankar K. Gloss B.S. Li Z. Street J.A. Moezzi L. Mach M.A. Sutrave G. Clancy L.E. Bishop D.C. et al. Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood. 2021; 138: 1391-1405 Crossref PubMed Scopus (58) Google Scholar ,2 Bishop D.C. Clancy L.E. Simms R. Burgess J. Mathew G. Moezzi L. Street J.A. Sutrave G. Atkins E. McGuire H.M. et al. Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood. 2021; 138: 1504-1509 Crossref PubMed Scopus (52) Google Scholar In evaluating possible mechanisms of transformation, it may be useful to consider the properties of transposition that differ from the more familiar retroviral integration and ask whether these could have influenced development of the two lymphomas. For example, transposon DNA integrated in a host chromosome can be a substrate for further rounds of excision and transposition, where each excision event generates a DNA double-strand break at the empty transposon-donor site. Transposases can also cleave genomic DNA directly at chromosomal sequences that, by chance, resemble transposase-binding sites. These mechanisms are described more fully below, and additional experiments are described that could help clarify possible pathways of genotoxicity and potentially mitigate risks. Response to: DNA transposon mechanisms and pathways of genotoxicityMadison et al.Molecular TherapyAugust 14, 2023In BriefWe would like to respond to a recent commentary by Frederic D. Bushman in the March 2023 issue of Molecular Therapy, speculating on the possible role of the piggyBac transposon in a CAR-T trial involving two lymphomas emerging from engineered CAR-T cells.1 Full-Text PDF
A third SARS-CoV-2 mRNA vaccine dose in people receiving hemodialysis overcomes B cell defects but elicits a skewed CD4+ T cell profile
Authors: Gérémy Sannier, Alexandre Nicolas, Mathieu Dubé, Lorie Marchitto, Manon Nayrac, Olivier Tastet, Debashree Chatterjee, Alexandra Tauzin, Raphaël Lima-Barbosa, Mélanie Laporte, Rose Cloutier, Alina M. Sreng Flores, Marianne Boutin, Shang Yu Gong, Mehdi Benlarbi, Shilei Ding, Catherine Bourassa, Gabrielle Gendron-Lepage, Halima Medjahed, Guillaume Goyette, Nathalie Brassard, Gloria-Gabrielle Delgado, Julia Niessl, Laurie Gokool, Chantal Morrisseau, Pascale Arlotto, Norka Rios, Cécile Tremblay, Valérie Martel-Laferrière, Alexandre Prat, Justin Bélair, William Beaubien-Souligny, Rémi Goupil, Annie-Claire Nadeau-Fredette, Caroline Lamarche, Andrés Finzi, Rita S. Suri, Daniel E. Kaufmann
Journal: Cell Reports Medicine (2023)

Cellular immune defects associated with suboptimal responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in people receiving hemodialysis (HD) are poorly understood. We longitudinally analyze antibody, B cell, CD4+, and CD8+ T cell vaccine responses in 27 HD patients and 26 low-risk control individuals (CIs). The first two doses elicit weaker B cell and CD8+ T cell responses in HD than in CI, while CD4+ T cell responses are quantitatively similar. In HD, a third dose robustly boosts B cell responses, leads to convergent CD8+ T cell responses, and enhances comparatively more T helper (TH) immunity. Unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. The third dose attenuates some features of TH cells in HD (tumor necrosis factor alpha [TNFα]/interleukin [IL]-2 skewing), while others (CCR6, CXCR6, programmed cell death protein 1 [PD-1], and HLA-DR overexpression) persist. Therefore, a third vaccine dose is critical to achieving robust multifaceted immunity in hemodialysis patients, although some distinct TH characteristics endure.
Nursing care for patients with cirrhosis
Authors: Núria Fabrellas, Patrizia Künzler-Heule, Amy Olofson, Kathryn Jack, Marta Carol
Journal: Journal of Hepatology (2023)

Cirrhosis represents a major cause of morbidity and mortality, leading to a marked impairment in the quality of life of patients and their caregivers, and resulting in a major burden on healthcare systems. Currently, in most countries, nurses still play a limited role in the care of patients with cirrhosis, which is mainly restricted to the care of patients hospitalised for acute complications of the disease. The current manuscript reviews the established and potential new and innovative roles that nurses can play in the care of patients with cirrhosis. In the hospital setting, specialised nurses should become an integral part of interprofessional teams, helping to improve the quality of care and outcomes of patients with cirrhosis. In the primary care setting, nurses should play an important role in the care of patients with compensated cirrhosis and also facilitate early diagnosis of cirrhosis in those at risk of liver diseases. This review calls for an improved global liver disease education programme for nurses and increased awareness among all healthcare providers and policymakers of the positive impacts of advanced or specialist nursing practice in this domain.
Revisiting nanoparticle transendothelial migration in the liver
Authors: Seyed Moein Moghimi, Rebecca McCullough, Dmitri Simberg
Journal: Molecular Therapy (2023)

The approval of Onpattro by the US Food and Drug Administration in 2018 1 Akinc A. Maier M.A. Manoharan M. Fitzgerald K. Jayaraman M. Barros S. Ansell S. Du X. Hope M.J. Madden T.D. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 2019; 14: 1084-1087https://doi.org/10.1038/s41565-019-0591-y Crossref PubMed Scopus (621) Google Scholar has stimulated much interest in lipid nanoparticles (LNPs) with ionisable cationic lipids for the delivery of gene medicines to hepatocytes. While physicochemical aspects of LNP formulations and their intracellular performance have been studied, 1 Akinc A. Maier M.A. Manoharan M. Fitzgerald K. Jayaraman M. Barros S. Ansell S. Du X. Hope M.J. Madden T.D. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 2019; 14: 1084-1087https://doi.org/10.1038/s41565-019-0591-y Crossref PubMed Scopus (621) Google Scholar there are limited studies on pathophysiological and physicochemical factors that modulate transendothelial migration of LNPs and related lipid-based carriers in human liver. Furthermore, LNP potency in the liver of widely used preclinical species such as rats and mice may not necessarily translate to successful clinical practice in humans since there are species and strain/substrain differences in hepatic endothelial/sinusoidal ultrastructure. 2 Snoeys J. Lievens J. Wisse E. Jacobs F. Duimel H. Collen D. Frederik P. De Geest B. Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae. Gene Ther. 2007; 14: 604-612https://doi.org/10.1038/sj.gt.3302899 Crossref PubMed Scopus (83) Google Scholar ,3 Wisse E. Jacobs F. Topal B. Frederik P. De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther. 2008; 15: 1193-1199https://doi.org/10.1038/gt.2008.60 Crossref PubMed Scopus (232) Google Scholar Pathophysiological conditions also modulate "liver sieve" performance. 4 Fraser R. Cogger V.C. Dobbs B. Jamieson H. Warren A. Hilmer S.N. Le Couteur D.G. The liver sieve and atherosclerosis. Pathology (Phila.). 2012; 44: 181-186https://doi.org/10.1097/PAT.0b013e328351bcc8 Abstract Full Text PDF Scopus (54) Google Scholar A more fundamental understanding of transendothelial migration of nanoparticles would be extremely useful to facilitate translation of LNPs for human liver gene therapy.
Local type 2 immunity in eosinophilic gastritis
Authors: Netali Ben-Baruch Morgenstern, Tetsuo Shoda, Yrina Rochman, Julie M. Caldwell, Margaret H. Collins, Vincent Mukkada, Philip E. Putnam, Scott M. Bolton, Jennifer M. Felton, Mark Rochman, Cristin Murray-Petzold, Kara L. Kliewer, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2023)
The chromatin-associated RNAs in gene regulation and cancer
Authors: Jun Tang, Xiang Wang, Desheng Xiao, Shuang Liu, Yongguang Tao
Journal: Molecular Cancer (2023)

Abstract Eukaryotic genomes are prevalently transcribed into many types of RNAs that translate into proteins or execute gene regulatory functions. Many RNAs associate with chromatin directly or indirectly and are called chromatin-associated RNAs (caRNAs). To date, caRNAs have been found to be involved in gene and transcriptional regulation through multiple mechanisms and have important roles in different types of cancers. In this review, we first present different categories of caRNAs and the modes of interaction between caRNAs and chromatin. We then detail the mechanisms of chromatin-associated nascent RNAs, chromatin-associated noncoding RNAs and emerging m 6 A on caRNAs in transcription and gene regulation. Finally, we discuss the roles of caRNAs in cancer as well as epigenetic and epitranscriptomic mechanisms contributing to cancer, which could provide insights into the relationship between different caRNAs and cancer, as well as tumor treatment and intervention.